Diabetes is a leading cause of morbidity and death in the United States. Type 2 diabetes, the most common form, is associated with obesity and characterized by resistance to the actions of insulin. Although the underiying mechanisms are complex and controversial, it is now clear that type 2 diabetes is a chronic inflammatory state, and that inflammation modulates glucose metabolism. We were first to describe a novel secreted protein called resistin that exacerbates insulin resistance. In mice, resistin is adipocyte-specific and expressed constitutively, but human resistin is produced predominantly by macrophages and induced by nflammatory stimuli. Epidemiologic and genetic evidence supports a role for resistin in human diabetes and cardiovascular disease, and we have demonstrated that macrophage-derived human resistin is sufficient to exacerbate diet-induced insulin resistance. However, the metabolic effects of inflammation-induced resistin are not known. We now have established an innovative humanized resistin model in which mice lacking mouse resistin express low circulating levels of resistin that increase with high fat diet and after exposure to endotoxin. Specific Aim 1 is to determine the impact of humanized resistin expression on obesity- and inflammation-associated insulin resistance. We hypothesize that humanized resistin expression induces insulin resistance that is chronically deleterious but protective hypoglycemia, and will evaluate this using innovative models of inflammation interrogated by glucose and insulin clamp studies. Specific Aim 2 is to determine the effects of humanized resistin expression on cardiovascular disease. We hypothesize that the humanized expression of resistin will exacerbate heart failure, and will test this in appropriate models. Specific Aim 3 is to detennine the mechanism of species- and cell-specificity of resistin expression, applying an innovative epigenomic discovery approach will to this important problem. Together, the proposed studies will address critical questions about the role of resistin as a link between inflammation, insulin resistance, and cardiometabolic diseases, and a potential target for intervention in these devastating diseases. These studies have important implications for our society in which metabolic diseases are rampant. RELEVANCE (See instructions): Diabetes is a leading cause of morbidity and death in the United States. Type 2 diabetes, the most common form of diabetes, is associated with obesity and characterized by resistance to the actions of insulin. Understanding the mechanism of insulin resistance is critical to finding new therapies. We are determining the role of resistin, which exacerbates insulin resistance and is induced by inflammation in humans. Resistin may be a target for novel therapies that stem the tide of the epidemic of metabolic disease in our society.